Hydrogel as well as preparation method and application thereof

Abstract

The invention provides hydrogel as well as a preparation method and application thereof, and belongs to the technical field of biomedical materials. The hydrogel provided by the invention is prepared from the following raw materials: chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N, N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy) ethyl] dimethylammonium] propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and an initiator in a mass ratio of (0.025 to 0.075): (0.0015 to 0.0040): (0.3 to 1.2): (0.3 to 1.2): (0.3 to 1.2): (0.03 to 0.12): 0.01. On the basis of electrostatic interaction among the components, phase separation polymerization is induced to prepare the hydrogel of which one side has strong viscosity and the other side is basically non-viscous.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials, and specifically relates to a hydrogel and a preparation method and application thereof. Background Art

[0002] Hydrogel wound dressings have the properties of providing a moist microenvironment, isolating the wound site from bacteria, loading drugs to relieve wound inflammation, sterilizing and disinfecting, stopping bleeding and accelerating wound healing. They have attracted much attention as an ideal substitute or auxiliary for suturing defective organs.

[0003] In order to ensure that the hydrogel can quickly adhere to the wound and block the bleeding point, the hydrogel must have high adhesion properties, but the prepared hydrogel adhesive has strong adhesion on both sides. During in vitro use, it is inevitable that it will come into contact with the outside world and adhere, affecting the normal use of the dressing. This requires that the hydrogel dressing must not only have strong adhesion to the injured tissue, but also have anti-adhesion properties with other normal tissues, that is, one side has strong adhesion, while the other side has no adhesion or weak adhesion. At present, anti-postoperative adhesion hydrogel dressings pay too much attention to anti-postoperative adhesion properties, while ignoring the adhesion properties of the adhesive, and have little application value.

[0004] Therefore, how to prepare a hydrogel that can both tightly adhere to moist tissues and prevent postoperative organ adhesion has become a technical problem that needs to be solved urgently in this field. Summary of the invention

[0005] The purpose of the present invention is to provide a hydrogel and its preparation method and application. The hydrogel provided by the present invention has strong viscosity on one side and can tightly adhere to moist tissue, and has substantially no viscosity on the other side and can prevent postoperative organ adhesion.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides a hydrogel, the raw materials of which include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, initiator and water;

[0008] The mass ratio of the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and the initiator is (0.025 - 0.075):(0.0015 - 0.0040):(0.3 - 1.2):(0.3 - 1.2):(0.3 - 1.2):(0.03 - 0.12):0.01.

[0009] Preferably, the ammoniation of the quaternary ammonium salt of chitosan is ≥90%.

[0010] Preferably, the mass ratio of the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and the initiator is (0.025 - 0.070):(0.0020 - 0.0035):(0.3 - 0.9):(0.3 - 0.9):(0.3 - 0.9):(0.05 - 0.10):0.01.

[0011] Preferably, the mass ratio of the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and the initiator is (0.025 - 0.050):(0.0025 - 0.0030):(0.5 - 0.6):(0.5 - 0.6):(0.5 - 0.6):(0.05 - 0.08):0.01.

[0012] The present invention also provides a preparation method of the hydrogel described in the above technical solution, including the following steps:

[0013] (1) Mix the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, the initiator and water to obtain a mixed solution;

[0014] (2) Carry out a polymerization reaction on the mixed solution obtained in the step (1) to obtain a hydrogel.

[0015] Preferably, the mixing of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethyl ammonium] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, initiator and water in the step (1) comprises the following steps:

[0016] 1) Mix chitosan quaternary ammonium salt and part of water to obtain a chitosan quaternary ammonium salt solution;

[0017] 2) Mix polyvinyl alcohol and the remaining water to obtain a polyvinyl alcohol solution;

[0018] 3) Mix the chitosan quaternary ammonium salt solution obtained in the step 1), the polyvinyl alcohol solution obtained in the step 2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethyl ammonium] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator;

[0019] There is no sequence requirement between the step 1) and the step 2).

[0020] Preferably, the concentration of the polyvinyl alcohol solution in the step 2) is 0.5-1.5 wt%.

[0021] Preferably, the polymerization reaction in the step (2) is carried out under ultraviolet light irradiation.

[0022] Preferably, the wavelength of the ultraviolet light is 385 nm, the power of the ultraviolet light is 18-54 W, and the irradiation time of the ultraviolet light is 3-10 min.

[0023] The present invention also provides the application of the hydrogel described in the above technical solution or the hydrogel prepared by the preparation method described in the above technical solution in medical dressings.

[0024] The present invention provides a hydrogel, the raw materials of which include quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, an initiator and water; the mass ratio of the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and the initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01. Based on the electrostatic interaction between the components, the present invention induces phase separation polymerization to prepare a hydrogel with strong adhesion on one side (able to tightly bond wet tissues) and substantially no adhesion on the other side (able to prevent postoperative organ adhesion). Among them, the quaternary ammonium salt of chitosan contains abundant ammonium cations, and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio] propane-1-sulfonate and acrylic acid contain sulfonic acid and carboxyl anions respectively. Through the electrostatic interaction of cations and anions, a large number of 3-[[2-(methacryloyloxy)ethyl]dimethylammonio] propane-1-sulfonate and acrylic acid molecules are adsorbed on the chitosan quaternary ammonium salt chain to generate macromolecular polymerization monomers. During the polymerization process, the molecular weights of these macromolecular polymerization monomers increase sharply, and their solubility in the system decreases, so they precipitate rapidly to form the lower layer of the hydrogel; while the remaining monomers not adsorbed on the chitosan quaternary ammonium salt (N-succinimidyl acrylate and N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide) polymerize to form the upper layer of the hydrogel; N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide has good solubility and barnacle-like adhesion, endowing the upper surface of the hydrogel with strong wet tissue adhesion performance; the quaternary ammonium salt of chitosan can make the hydrogel have high biocompatibility, strong antibacterial performance and hemostatic performance; polyvinyl alcohol helps the swelling behavior of the hydrogel, enabling it to rapidly expand after absorbing water to form a moist environment, which is beneficial to cell growth and tissue repair; N-succinimidyl acrylate can carry out amine-ester exchange reaction with the bonding tissue to quickly realize the bonding of the hydrogel and the tissue. The experimental results show that the adhesion strength of the upper surface of the hydrogel provided by the present invention is 87.762-149.582 J / m 2 , and the adhesion strength of the lower surface is 0-24.43 J / m 2; The contact angle of the upper surface is 87-102°; the contact angle of the lower surface is 61-77°; the antibacterial rate against Escherichia coli is more than 80%; the antibacterial rate against Staphylococcus aureus is more than 70%; the hemostatic amount of the mouse liver is 16.93-64.44 g, and the hemostatic time is 128.67-192.33 s. Description of the Drawings

[0025] Figure 1 It is the NMR spectrum of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide in Example 1;

[0026] Figure 2 It is the SEM image of the upper surface of the hydrogel prepared in Example 1;

[0027] Figure 3 It is the SEM image of the lower surface of the hydrogel prepared in Example 1;

[0028] Figure 4 It is the SEM image of the upper surface of the hydrogel prepared in Example 2;

[0029] Figure 5 It is the SEM image of the lower surface of the hydrogel prepared in Example 2;

[0030] Figure 6 It is the SEM image of the upper surface of the hydrogel prepared in Example 3;

[0031] Figure 7 It is the SEM image of the lower surface of the hydrogel prepared in Example 3. Detailed Embodiments

[0032] The present invention provides a hydrogel, and the raw materials include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, initiator and water;

[0033] The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01.

[0034] The present invention places no special restrictions on the sources of the raw materials, and commercially available products well-known to those skilled in the art can be used.

[0035] The raw materials for preparing the hydrogel of the present invention include chitosan quaternary ammonium salt; the ammoniation of the chitosan quaternary ammonium salt is preferably ≥90%. In the present invention, the chitosan quaternary ammonium salt contains abundant ammonium cations, which can generate macromolecular polymerization monomers through the electrostatic interaction of anions and cations with 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid. During the polymerization process, the molecular weights of these macromolecular polymerization monomers increase sharply, and their solubility in the system decreases, so they precipitate rapidly to form the lower layer of the hydrogel; while the remaining monomers not adsorbed on the chitosan quaternary ammonium salt (acrylic acid-N-succinimidyl ester and N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide) polymerize to form the upper layer of the hydrogel; in addition, the chitosan quaternary ammonium salt can endow the hydrogel with high biocompatibility, strong antibacterial properties and hemostatic properties.

[0036] The raw materials for preparing the hydrogel of the present invention further include polyvinyl alcohol; the molecular weight of the polyvinyl alcohol is preferably 50000-100000 g / mol. In the present invention, the polyvinyl alcohol contributes to the swelling behavior of the hydrogel, enabling it to rapidly expand after absorbing water to form a moist environment, which is beneficial to cell growth and tissue repair.

[0037] The raw materials for preparing the hydrogel of the present invention further include N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide. In the present invention, the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide has the ability to wet and bond like barnacles. Based on the principle of macro-phase separation polymerization induced by electrostatic interaction, it is located in the upper layer of the hydrogel, so the upper layer of the hydrogel has bonding properties, while the lower surface has no bonding properties.

[0038] In the present invention, the structural formula of the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide is as shown in Formula I:

[0039]

[0040] In the present invention, the preparation method of the N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide preferably includes the following steps:

[0041] Mix 4-(bromomethyl)phenylboronic acid, 2-(dimethylamino)ethyl acrylate and an organic solvent, and carry out an ammoniation reaction to obtain N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide.

[0042] In the present invention, the mass ratio of the 4-(bromomethyl)phenylboronic acid to the 2-(dimethylamino)ethyl acrylate is preferably (2-3):(1-2). As an embodiment, the mass ratio of the 4-(bromomethyl)phenylboronic acid to the 2-(dimethylamino)ethyl acrylate can be 2.5:1.57.

[0043] In the present invention, the organic solvent is preferably tetrahydrofuran. The present invention has no special limitation on the amount of the organic solvent used, as long as the raw materials can be completely dissolved.

[0044] The present invention has no special limitation on the operation of mixing the 4-(bromomethyl)phenylboronic acid, the 2-(dimethylamino)ethyl acrylate and the organic solvent, and the technical solutions for preparing the mixed material well-known to those skilled in the art can be adopted.

[0045] In the present invention, the temperature of the ammoniation reaction is preferably room temperature; the time of the ammoniation reaction is preferably 20-25 h, more preferably 24 h; the ammoniation reaction is preferably carried out under sealed conditions. The present invention limits the temperature and time of the ammoniation reaction within the above ranges to further improve the reaction degree.

[0046] After the ammoniation reaction is completed, the present invention preferably filters, washes and dries the product obtained from the ammoniation reaction to obtain N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide.

[0047] In the present invention, the filtration is preferably suction filtration. The present invention has no special limitation on the operation of the suction filtration, and the operations well-known to those skilled in the art can be adopted.

[0048] The present invention has no special limitation on the operation of the washing, and the operations well-known to those skilled in the art can be adopted.

[0049] The present invention has no special limitation on the operation of the drying, and it can be dried to a constant weight.

[0050] The raw materials for preparing the hydrogel of the present invention further include 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate. In the present invention, the 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate contains sulfonic acid anions, and through the electrostatic interaction of anions and cations, it is adsorbed on the chitosan quaternary ammonium salt chain to generate macromolecular polymerization monomers. During the polymerization process, the molecular weights of these macromolecular polymerization monomers increase sharply, and their solubility in the system decreases, so they precipitate rapidly to form the lower layer of the hydrogel.

[0051] The raw materials for preparing the hydrogel of the present invention further include acrylic acid. In the present invention, the acrylic acid contains carboxylate anions, which are adsorbed on the chitosan quaternary ammonium salt chain through the electrostatic interaction between anions and cations to generate macromolecular polymerization monomers. During the polymerization process, the molecular weights of these macromolecular polymerization monomers increase sharply, and their solubility in the system decreases, so they precipitate quickly to form the lower layer of the hydrogel.

[0052] The raw materials for preparing the hydrogel of the present invention further include N-succinimidyl acrylate. In the present invention, the N-succinimidyl acrylate is not adsorbed on the chitosan quaternary ammonium salt, so the upper layer of the hydrogel is polymerized; at the same time, N-succinimidyl acrylate is an adhesive, which can carry out aminolysis reaction with the adhesive tissue to quickly realize the adhesion between the hydrogel and the tissue, and can further improve the adhesion of the upper layer of the hydrogel compared with other adhesives.

[0053] The raw materials for preparing the hydrogel of the present invention further include an initiator; the initiator is preferably at least one of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, lithium phenyl-2,4,6-trimethylbenzoylphosphinate and KIPEM photoinitiator. In the present invention, the initiator is used to initiate the polymerization reaction.

[0054] The raw materials for preparing the hydrogel of the present invention further include water. In the present invention, the water is a solvent for dissolving each raw material.

[0055] The present invention has no special limitation on the amount of water used, as long as each raw material can be completely dissolved.

[0056] In the present invention, the mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and the initiator is (0.025-0.075):(0.0015-0.0040):(0.3-1.2):(0.3-1.2):(0.3-1.2):(0.03-0.12):0.01. The present invention limits the mass ratio of each raw material within the above range to obtain a hydrogel with strong adhesion on one side (able to tightly adhere to wet tissue) and basically no adhesion on the other side (able to prevent postoperative organ adhesion).

[0057] As an implementation mode, the mass ratio of the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator can be (0.025 - 0.070):(0.0020 - 0.0035):(0.3 - 0.9):(0.3 - 0.9):(0.3 - 0.9):(0.05 - 0.10):0.01, and can also be (0.025 - 0.050):(0.0025 - 0.0030):(0.5 - 0.6):(0.5 - 0.6):(0.5 - 0.6):(0.05 - 0.08):0.01.

[0058] Based on the electrostatic interaction between the components, the present invention induces phase separation polymerization to prepare a hydrogel with strong adhesion on one side (able to tightly bond wet tissues) and basically no adhesion on the other side (able to prevent postoperative organ adhesion). Among them, the quaternary ammonium salt of chitosan contains abundant ammonium cations, and 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid contain sulfonic acid and carboxyl anions respectively. Through the electrostatic interaction of anions and cations, a large number of 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid molecules are adsorbed on the chitosan quaternary ammonium salt chain to form macromolecular polymerization monomers. During the polymerization process, the molecular weights of these macromolecular polymerization monomers increase sharply, and their solubility in the system decreases, so they quickly precipitate to form the lower layer of the hydrogel; while the remaining monomers not adsorbed on the chitosan quaternary ammonium salt (N-succinimidyl acrylate and N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide) polymerize to form the upper layer of the hydrogel; N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide has good solubility and barnacle-like adhesion, endowing the upper surface of the hydrogel with strong wet tissue adhesion performance; the quaternary ammonium salt of chitosan can make the hydrogel have high biocompatibility, strong antibacterial performance and hemostatic performance; polyvinyl alcohol helps the swelling behavior of the hydrogel, enabling it to quickly expand after absorbing water to form a moist environment, which is beneficial to cell growth and tissue repair.

[0059] The upper surface of the hydrogel provided by the present invention can firmly adhere to the tissue defect, and the maximum adhesion strength can reach 149.582 J / m 2 , while the other opposite surface has no obvious adhesion to wet tissues, can effectively solve the postoperative adhesion problem, can be used as a wound sealant, and can well prevent postoperative adhesion.

[0060] The present invention also provides a preparation method of the hydrogel described in the above technical solution, including the following steps:

[0061] (1) Mix chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethyl ammonium] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, initiator and water to obtain a mixed solution;

[0062] (2) Carry out a polymerization reaction on the mixed solution obtained in the step (1) to obtain a hydrogel.

[0063] In the present invention, chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethyl ammonium] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, initiator and water are mixed to obtain a mixed solution.

[0064] In the present invention, the mixing of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethyl ammonium] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, initiator and water preferably includes the following steps:

[0065] 1) Mix chitosan quaternary ammonium salt and a part of water to obtain a chitosan quaternary ammonium salt solution;

[0066] 2) Mix polyvinyl alcohol and the remaining water to obtain a polyvinyl alcohol solution;

[0067] 3) Mix the chitosan quaternary ammonium salt solution obtained in the step 1), the polyvinyl alcohol solution obtained in the step 2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethyl ammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethyl ammonium] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator;

[0068] There is no sequence priority between the step 1) and the step 2).

[0069] The present invention preferably mixes chitosan quaternary ammonium salt and a part of water to obtain a chitosan quaternary ammonium salt solution.

[0070] In the present invention, the mass-volume ratio of the chitosan quaternary ammonium salt to the part of water is preferably (0.025-0.075) g:(1.5-3.5) mL, more preferably 0.025 g:2.5 mL.

[0071] The present invention has no special limitation on the operation of mixing the quaternary ammonium salt of chitosan and part of water, and the technical solution for preparing the mixed material well-known to those skilled in the art can be adopted.

[0072] The present invention preferably mixes polyvinyl alcohol and the remaining water to obtain a polyvinyl alcohol solution.

[0073] The present invention has no special limitation on the operation of mixing the polyvinyl alcohol and the remaining water, and the technical solution for preparing the mixed material well-known to those skilled in the art can be adopted.

[0074] In the present invention, the concentration of the polyvinyl alcohol solution is preferably 0.5 - 1.5 wt%, more preferably 1 wt%.

[0075] After obtaining the quaternary ammonium salt solution of chitosan and the polyvinyl alcohol solution, the present invention preferably mixes the quaternary ammonium salt solution of chitosan, the polyvinyl alcohol solution, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethylammonio] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and an initiator.

[0076] The present invention has no special limitation on the operation of mixing the quaternary ammonium salt solution of chitosan, the polyvinyl alcohol solution, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethylammonio] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and an initiator, and the technical solution for preparing the mixed material well-known to those skilled in the art can be adopted.

[0077] After obtaining the mixed solution, the present invention carries out a polymerization reaction on the mixed solution to obtain a hydrogel.

[0078] In the present invention, the polymerization reaction is preferably carried out under ultraviolet light irradiation; the wavelength of the ultraviolet light is preferably 385 nm; the power of the ultraviolet light is preferably 18 - 54 W, more preferably 36 W; the time of ultraviolet light irradiation is preferably 3 - 10 min, more preferably 3 - 5 min. Limiting the process parameters of the polymerization reaction within the above ranges can further improve the degree of the polymerization reaction.

[0079] Based on the electrostatic interaction between the components, the present invention induces phase separation polymerization to prepare a hydrogel with asymmetric viscosity, and the process is simple.

[0080] The present invention also provides the application of the hydrogel described in the above technical solution or the hydrogel prepared by the preparation method described in the above technical solution in a medical dressing.

[0081] The present invention has no special limitation on the operation of applying the hydrogel in a medical dressing, and the operations well-known to those skilled in the art can be adopted.

[0082] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0083] Example 1

[0084] The raw materials of the hydrogel are quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate, initiator and water;

[0085] The molecular weight of the polyvinyl alcohol is 50000-100000 g / mol;

[0086] The initiator is 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone;

[0087] The ammoniation of the quaternary ammonium salt of chitosan is 90%, provided by Wuhan Lanabai Pharmaceutical Chemical Co., Ltd.;

[0088] The structural formula of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide is:

[0089]

[0090] The preparation method of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide is as follows: Dissolve 2.5 g of 4-(bromomethyl)phenylboronic acid in 100 mL of tetrahydrofuran, add 1.57 g of 2-(dimethylamino)ethyl acrylate, seal and stir at room temperature for 24 h for ammoniation reaction, then filter by suction, wash the precipitate with tetrahydrofuran three times, and then dry at 50 °C under vacuum for 24 h to obtain white powder N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide;

[0091] The mass ratio of the quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator is 0.025:0.0025:0.3:0.6:0.6:0.05:0.01;

[0092] The preparation method of the hydrogel comprises the following steps:

[0093] (1) Stir the quaternary ammonium salt of chitosan and part of water at room temperature for 5 h to obtain a quaternary ammonium salt solution of chitosan; wherein, the mass ratio of the quaternary ammonium salt of chitosan to the volume of part of water is 0.025 g:2.5 mL;

[0094] (2) Mix polyvinyl alcohol and the remaining water to obtain a polyvinyl alcohol solution; wherein, the concentration of the polyvinyl alcohol solution is 1 wt%;

[0095] (3) Stir the quaternary ammonium salt solution of chitosan obtained in (1), the polyvinyl alcohol solution obtained in step (2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator for 1 h to obtain a transparent mixed solution;

[0096] (4) Irradiate the mixed solution obtained in step (3) with ultraviolet light at a wavelength of 385 nm and a power of 36 W for 3 min to carry out a polymerization reaction to obtain a hydrogel.

[0097] The equation for preparing N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide in Example 1 is as follows:

[0098]

[0099] The NMR spectrum of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide in Example 1 is as Figure 1 shown.

[0100] From Figure 1 it can be seen that N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide was prepared in Example 1 of the present invention.

[0101] Example 2

[0102] On the basis of Example 1, the mass ratio of quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethylammonio] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator was modified to 0.025:0.0025:0.6:0.6:0.6:0.05:0.01, and other conditions remained unchanged.

[0103] Example 3

[0104] On the basis of Example 1, the mass ratio of quaternary ammonium salt of chitosan, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl] dimethylammonio] propane-1-sulfonate, acrylic acid, N-succinimidyl acrylate and initiator was modified to 0.025:0.0025:0.9:0.6:0.6:0.05:0.01, and other conditions remained unchanged.

[0105] The hydrogels prepared in Examples 1 to 3 were subjected to performance tests, and the test methods were as follows:

[0106] 1. Contact angle test: A drop of deionized water was dropped on the upper and lower surfaces of the hydrogel, and the contact angle between the liquid drop and the hydrogel surface was measured with a contact angle meter (OCA200, Data Physics, Germany). The results are shown in Table 1.

[0107] 2. Adhesive performance test: Using the 180° peel test method, the adhesion strength of the hydrogel was tested on a universal tester (XLW(PC), Samsung, China). A coupling agent (12 mg / mL, 50 μL, EDC:NHS = 1:1 (w / w)) was applied to the bottom of the hydrogel (length = 40 mm, width = 10 mm, thickness = 1.5 mm). Then, the hydrogel coated with the coupling agent was pressed onto the matrix tissue (length = 60 mm, width = 15 mm) under a weight of 500 g. A polyethylene terephthalate (PET) film (the same size as the substrate tissue) was used as the hydrogel backing. The universal tester applied a unidirectional tension while recording the changes in force (F) and displacement, and the loading rate was kept constant at 50 mm / min. The interfacial toughness was calculated as the ratio of 2F to the width of the hydrogel. These data were reported as mean ± 1 standard deviation (n = 5). The results are shown in Table 1.

[0108] 3. Bacteriostatic performance test: 2 mg of the hydrogel was added to a glass bottle, and the logarithmic growth phase of Escherichia coli (ATCC25922) was diluted to 10 6CFU. Then, 10 mL of Escherichia coli solution was co-cultured with the hydrogel, added at 1, 3, 5, 7, and 9 h, and incubated in a constant temperature incubator at 37 °C. After co-culture, 100 μL of the solution was cultured on an LB solid medium in a constant temperature incubator at 37 °C for 24 h. Single colonies were counted and compared with the control group. Staphylococcus aureus was also used under the same protocol. The antibacterial rate I was calculated according to Equation II:

[0109]

[0110] In Equation II, C 0 is the antibacterial rate of the blank group, and C 1 is the antibacterial rate of the experimental group. The antibacterial properties are shown in Tables 2 and 3.

[0111] 4. Hemostasis performance test: Rats were anesthetized by intraperitoneal injection of 4% chloral hydrate (100 g / mL) and fixed on the operating board. The rat liver was exposed through an abdominal incision. The tissue fluid around the liver was carefully removed with a medical gauze, and a medical gauze was placed under the liver. A 1.5-cm long and 0.25-cm deep incision was made in the middle lobe of the liver with a scalpel. Then, the wound was covered with a gauze and the hydrogel. After complete hemostasis, the weight of the blood absorbed by the filter paper was weighed and compared with the control group. Each group was performed 3 times. All animal experiments were carried out in accordance with the current experimental animal care guidelines. The hemostasis performance data are shown in Table 4.

[0112] Table 1 Adhesiveness and hydrophilicity of the upper and lower surfaces of the hydrogels prepared in Examples 1 to 3

[0113]

[0114]

[0115] Table 2 Antibacterial properties of the hydrogels prepared in Examples 1 to 3 against Escherichia coli

[0116]

[0117] Table 3 Antibacterial properties of the hydrogels prepared in Examples 1 to 3 against Staphylococcus aureus

[0118]

[0119] Table 4 Hemostasis performance of the hydrogels prepared in Examples 1 to 3

[0120] Serial number Hemostasis amount of mouse liver (g) Hemostasis time of mouse liver (s) Gauze 249.37 198.33 Example 1 16.93 128.67 Example 2 26.93 154.67 Example 3 64.44 192.33

[0121] As can be seen from Tables 1 to 4, the hydrogel provided by the present invention has strong adhesiveness on one side and basically no adhesiveness on the other side; and has excellent antibacterial, hemostasis, and hydrophilic properties.

[0122] The SEM image of the upper surface of the hydrogel prepared in Example 1 is as shown in Figure 2 ; the SEM image of the lower surface of the hydrogel prepared in Example 1 is as shown in Figure 3 ; the SEM image of the upper surface of the hydrogel prepared in Example 2 is as shown in Figure 4 ; the SEM image of the lower surface of the hydrogel prepared in Example 2 is as shown in Figure 5 ; the SEM image of the upper surface of the hydrogel prepared in Example 3 is as shown in Figure 6 ; the SEM image of the lower surface of the hydrogel prepared in Example 3 is as shown in Figure 7 .

[0123] It can be seen from Figures 2 to 7 that both the upper and lower surfaces of the hydrogel are porous structures, with larger pore sizes on the upper surface and smaller pore sizes on the lower surface; as the dosage of N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide increases, the pore size difference between the upper and lower surfaces becomes smaller; although N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl)N,N-dimethylammonium bromide has a cation-π bond structure and a large steric hindrance, a large dosage will also cause strong electrostatic interactions with 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propane-1-sulfonate and acrylic acid, making the molecular chain arrangement denser.

[0124] It can be seen from the above examples that the hydrogel provided by the present invention has strong adhesiveness on one side and can tightly bond to wet tissues, and has basically no adhesiveness on the other side, which can prevent postoperative organ adhesion.

[0125] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A hydrogel, the raw materials of which include chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, an initiator and water; The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.075): (0.0015-0.0040): (0.3-1.2): (0.3-1.2): (0.3-1.2): (0.03-0.12): 0.

01.

2. The hydrogel according to claim 1, characterized in that The ammonium salt content of the chitosan quaternary ammonium salt is ≥90%.

3. The hydrogel according to claim 1, characterized in that The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.070):(0.0020-0.0035):(0.3-0.9):(0.3-0.9):(0.3-0.9):(0.05-0.10):0.

01.

4. The hydrogel according to claim 1 or 3, characterized in that The mass ratio of the chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and initiator is (0.025-0.050):(0.0025-0.0030):(0.5-0.6):(0.5-0.6):(0.5-0.6):(0.05-0.08):0.

01.

5. The method for preparing the hydrogel according to any one of claims 1 to 4, comprising the following steps: (1) mixing chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimidyl ester, an initiator and water to obtain a mixed solution; (2) subjecting the mixed solution obtained in step (1) to a polymerization reaction to obtain a hydrogel.

6. The preparation method according to claim 5, characterized in that: In the step (1), the mixing of chitosan quaternary ammonium salt, polyvinyl alcohol, N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester, initiator and water comprises the following steps: 1) mixing chitosan quaternary ammonium salt and part of water to obtain a chitosan quaternary ammonium salt solution; 2) mixing polyvinyl alcohol and remaining water to obtain a polyvinyl alcohol solution; 3) mixing the chitosan quaternary ammonium salt solution obtained in step 1), the polyvinyl alcohol solution obtained in step 2), N-(2-acryloyloxyethyl)-N-(4-phenylboronic acid methyl) N,N-dimethylammonium bromide, 3-[[2-(methacryloyloxy)ethyl]dimethylammonium]propane-1-sulfonate, acrylic acid, acrylic acid-N-succinimide ester and an initiator; There is no order of precedence for steps 1) and 2).

7. The preparation method according to claim 6, characterized in that: The concentration of the polyvinyl alcohol solution in step 2) is 0.5-1.5 wt %.

8. The preparation method according to claim 5, characterized in that: The polymerization reaction in step (2) is carried out under ultraviolet light irradiation.

9. The preparation method according to claim 8, characterized in that: The wavelength of the ultraviolet light is 385nm, the power of the ultraviolet light is 18-54W, and the ultraviolet light irradiation time is 3-10min.

10. Use of the hydrogel according to any one of claims 1 to 4 or the hydrogel prepared by the preparation method according to any one of claims 5 to 9 in medical dressings.

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